Abstract
497
Objectives Dysfunctional neurotransmission through the dopamine-D2 (D2R) and dopamine-D3 (D3R) receptors is implicated in a variety of neuropsychiatric disorders. In vitro assays found ~20-fold higher affinity for dopamine (DA) at the D3R compared to the D2R 1, but in vivo data is lacking. We quantified the regional binding of [11C]-(+)-PHNO in the brains of 7 male volunteers, following the administration of a single oral dose of d-amphetamine (AMP; 0.3mg/kg), to estimate the relative affinity of DA at D3R and D2R. We assumed that the magnitude of AMP induced increase in extracellular DA was similar in striatal and extra-striatal regions of interest (ROI)2.
Methods Each volunteer was scanned with [11C]-(+)-PHNO on two occasions, >7 days apart. The second [11C]-(+)-PHNO scan occurred 3 hours after AMP administration, and injected mass of (+)-PHNO was well matched between the two scans. PET emission data was collected over 90 min, and regional BPND data was quantified via a simplified reference tissue model with a cerebellar reference region. The effect of d-amphetamine (ΔBPND) was quantified in the Putamen (Put), Caudate, (Cau), Ventral Striatum (VST), Globus Pallidus (GP), Ventral Pallidum (VP), Thalamus (Th), Hypothalamus (HTh) and Substantia Nigra &Ventral Tegmental Area (SN&VTA)3. Regional ΔBPND was regressed against the fD3PHNO, the relative fraction of the [11C]-(+)-PHNO BPND attributable to the D3R, derived from previous work 3. ΔBPND=fD3PHNO(ΔBPNDD3 - ΔBPNDD2high )+ ΔBPNDD2high
Results The regression model was statistically significant (r = 0.325, p = 0.014), with estimated ΔBPNDD3 = 0.221 and ΔBPNDD2high = 0.106 (where ΔBPND =ΔDA/(ΔDA+KdDA)), indicating that KDAD2high/KDAD3 =2.3.
Conclusions The selectivity of DA for the D3R in vivo is an order of magnitude lower than that estimated in vitro. This conclusion is maintained when non-tracer binding of (+)-PHNO at the D3R but not at the D2R is accounted for. 1 Levesque, PNAS 1992 2 Robertson, J Neurosci 1991 3 Tziortzi, Neuroimage 2010
Research Support GlaxoSmithKlin